The University of Texas-Houston (UTH) Medical School and collaborating clinical and basic investigators at the UT-M.D. Anderson Cancer Center and the UTH-School of Public Health (Human Genetics Center) propose to establish a Center of Research Translation in Scleroderma (systemic sclerosis or SSc) or UTHCORT- SSc. The Director will be Frank C. Arnett, M.D. and the Associate Director Maureen D. Mayes, MD, MPH. SSc is a devastating human disease with high mortality and no effective treatment characterized by diffuse cutaneous and visceral fibrosis and vascular damage. The pathogenesis of SSc is unknown, however, there is evidence for both genetic and environmental influences. Thus, the central theme of UTHCORT- SSc is the use of molecular approaches (SNP genotyping of candidate genes and DNA microarrays) to understanding pathogenetic mechanisms, especially genetic factors, and the predictors of outcomes in SSc and translating them into improved medical care for patients with this disease. Two translational clinical and one basic research projects and two cores are proposed, as follows: 1) A functional genomics approach to defining genes and their molecular pathways in SSc fibroblasts, whole skin and peripheral blood cells utilizing DNA microarrays, RNA silencing and single nucleotide polymorphisms (SNP) association studies in a large multiethnic cohort of SSc patients;2) a large study of potential demographic, clinical, autoantibody and genetic predictors (including microarrays) of disease outcomes in three ethnic groups (Caucasians, African-Americans and Mexican-Americans);3) basic investigations, including genomic methods as in #1 (above), and comparisons with human SSc of two transgenic murine models of fibrosis (TGF(3 receptor and connective tissue growth factor (CTGF) over expressers;4) a Blood and Tissue Processing Core to process and store PBCs, skin biopsies and cultured fibroblasts from SSc patients;and 5) an Administrative Core for facilitating UTH-CORT-SSc translational research activities and selecting novel Pilot and Feasibility studies. The studies proposed here will provide better understanding of both the fundamental pathogenetic mechanisms and potentially useful clinical predictors of outcome in SSc which will lead to more directed therapies and/or disease prevention. Lay summary: Scleroderma (SSc) is a devastating disease of unknown cause which causes thickening of the skin and internal organs and high mortality which affects 3 in 10,000 Americans. The complex interactions of multiple genes will be studied in this CORT using blood and skin biopsies from SSc patients and mouse models of SSc. The aims are to find the cellular pathways causing disease and means to interrupt them, thus leading to new treatments or even prevention for this currently untreatable disease.